Isonitramine

 

 

Isonitramine

Organic Letters 2012, 14, 852

Y. Park, Y. J. Lee, S. Hong, M. Lee, H. Park*

The retrosynthesis of isonitramine begins with the unmasking of the amine (from the amide) and the alcohol (from the ketone).  The diphenylmethyl protection on amine 11 was removed by hydrogenation and amide 10 was reduced by lithium aluminum hydride reduction.  Amide 10 was prepared by the stereoselective reduction of the ketone group in 9 by Dibal-H.  The Al coordinates on the side containing the amide oxygen while delivering the hydride ion, thus giving the R configuration on secondary alcohol in 10.  Ketone 9 was derived by decarboxylation of ketoester 8, which is the Robinson annulation product of diester 7.  At this stage, there is a protecting group interchange in 6.  Compound 6 is derived by xanthate group removal from 5, which in turn is coming from the radical addition of xanthate and “ethylacetate anion” across the carbon-carbon double bond in 4.  Compound 4 is prepared from bromide 3 (because the non-brominated version did not give high ee).  The synthesis of compound 3 is what drives this synthesis – the “phase transfer catalyst” driven asymmetric allylation of alpha-tertbutoxycarbonyllactam compound 2.  A chiral PTC is used which gives the product is highly stereoselective fashion, but it required the 2-bromoallyl bromide instead of allyl bromide.  This is an example of the utility of “Br” as a masked “H” to improve stereoselectivity.  Compound 2 is prepared by installing the butoxycarbonyl group on valerolactam.

I noticed that all but 2 steps had >90% yield (and those two were also >85%)!!  Although most steps are fairly standard, but I still find it very impressive – especially when considering the messy “tin chemistry” and the final two reduction steps.